KR20020000642A - Use of Phthalazine Derivatives - Google Patents
Use of Phthalazine Derivatives Download PDFInfo
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- KR20020000642A KR20020000642A KR1020017014342A KR20017014342A KR20020000642A KR 20020000642 A KR20020000642 A KR 20020000642A KR 1020017014342 A KR1020017014342 A KR 1020017014342A KR 20017014342 A KR20017014342 A KR 20017014342A KR 20020000642 A KR20020000642 A KR 20020000642A
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Abstract
본 발명은 효소인 폴리(ADP-리보스) 폴리머라제 또는 PARP (EC 2.4.2.30)의 억제제로서의 프탈라진 유도체의 용도에 관한 것이고, PARP 상동성 효소의 억제제로서의 프탈라진 유도체의 용도에 관한 것이다. 또한 상기 유도체는 특히 PARP 상동성 효소를 선택적으로 억제한다.The present invention relates to the use of phthalazine derivatives as inhibitors of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.30) and to the use of phthalazine derivatives as inhibitors of PARP homologous enzymes. . The derivatives also selectively inhibit, in particular, PARP homologous enzymes.
Description
본 발명은 효소인 폴리(ADP-리보스) 폴리머라제 또는 PARP (EC 2.4.2.30)의 억제제로서의 프탈라진 유도체의 용도에 관한 것이고, 또한 상기 유도체는 특히 PARP 상동성 효소를 선택적으로 억제하므로 PARP 상동성 효소의 억제제로서의 프탈라진 유도체의 용도에 관한 것이다.The present invention relates to the use of phthalazine derivatives as inhibitors of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.30), which also specifically inhibits PARP homologous enzymes and thus on PARP Phthalazine derivatives as inhibitors of isoenzymes.
폴리(ADP-리보스) 신타제 (PARS)라고도 알려져 있는 폴리(ADP-리보스) 폴리머라제 (PARP)는 세포 핵에서 발견되는 조절 효소이다 (문헌 [K. Ikai et al., J. Histochem. Cytochem. 1983, 31, 1261-1264] 참조). PARP는 DNA 파괴 복구에 관여하는 것으로 추측된다 (문헌 [M.S. Satoh et al., Nature 1992, 356, 356-358] 참조). DNA 가닥의 손상 또는 파괴는 PARP 효소를 활성화시키고, 이렇게 활성화된 효소는 NAD로부터 ADP-리보스의 전달을 촉매한다 (문헌 [S. Shaw, Adv. Radiat. Biol., 1984, 11, 1-69] 참조). 이러는 동안, 니코틴아미드가 NAD로부터 방출된다. 니코틴아미드는 다른 효소에 의해 에너지 운반체인 ATP를 소비하면서 NAD로 다시 전환된다. 그러므로, PARP의 과활성화는 비생리적으로 다량의 ATP를 소비하게 될 것이며, 이는 극한 경우, 세포 손상 및 세포 사멸을 초래한다.Poly (ADP-ribose) polymerase (PARP), also known as poly (ADP-ribose) synthase (PARS), is a regulatory enzyme found in the cell nucleus (K. Ikai et al., J. Histochem. Cytochem. 1983, 31, 1261-1264). PARP is believed to be involved in repairing DNA destruction (see M.S. Satoh et al., Nature 1992, 356, 356-358). Damage or destruction of the DNA strands activates the PARP enzyme, which activates the transfer of ADP-ribose from the NAD (S. Shaw, Adv. Radiat. Biol., 1984, 11, 1-69). Reference). During this time nicotinamide is released from the NAD. Nicotinamide is converted back to NAD by another enzyme, consuming ATP, the energy carrier. Therefore, overactivation of PARP will consume a large amount of ATP nonphysiologically, which in extreme cases leads to cell damage and cell death.
과산화 음이온, NO 및 과산화수소 등과 같은 유리 라디칼이 세포에서 DNA 손상을 초래하여 PARP를 활성화시킬 수 있음은 공지되어 있다. 다량의 유리 라디칼형성이 여러 병태생리적 상태에서 관측되는데, 이로부터 이러한 유리 라디칼의 축적이 관측 세포 또는 기관의 손상을 일으키거나 이에 기여한다고 추측된다. 이러한 상태에는 예를 들어, 졸중, 심근경색에서 기관의 허혈 상태 (문헌 [C. Thiemermann et al., Proc. Natl. Acad. Sci. USA, 1997, 94, 679-683] 참조) 또는 신장의 허혈증 뿐 아니라, 예를 들면, 심근경색의 라이시스 (lysis) 후에 발생하는 것과 같은 재관류 손상 (상기 문헌 [C. Thiemermann et al.] 참조) 등이 포함된다. 그러므로, PARP 효소의 억제는 이러한 손상을 적어도 부분적으로 예방 또는 완화하는 수단이 될 수 있다. 그러므로, PARP 억제제는 여러 질병을 치료하는 신규 치료 성분이 될 수 있다.It is known that free radicals such as anion peroxide, NO and hydrogen peroxide can cause DNA damage in cells to activate PARP. Large amounts of free radical formation are observed in various pathophysiological states, from which it is speculated that the accumulation of these free radicals causes or contributes to damage to the observed cells or organs. Such conditions include, for example, stroke, ischemic status of organs in myocardial infarction (see C. Thiemermann et al., Proc. Natl. Acad. Sci. USA, 1997, 94, 679-683) or kidney ischemia. As well as, for example, reperfusion injury (see C. Thiemermann et al., Supra), such as occurs after lysis of myocardial infarction. Therefore, inhibition of the PARP enzyme may be a means to at least partially prevent or alleviate such damage. Therefore, PARP inhibitors can be novel therapeutic ingredients for treating various diseases.
PARP 효소는 DNA 손상 복구에 영향을 주며, 또한 세포증식억제 활성이 있는 물질과 함께 사용할 때 종양 조직에 대해 더 큰 활성 전위가 관측되었기 때문에 암 요법에서 역할을 할 수 있다 (문헌 [G. Chen et al., Cancer Chemo. Pharmacol. 1988, 22, 303] 참조).PARP enzymes affect the repair of DNA damage and may also play a role in cancer therapy because greater activity potentials have been observed for tumor tissues when used with substances that have cytostatic activity (G. Chen et al. al., Cancer Chemo. Pharmacol. 1988, 22, 303).
또한, PARP 억제제가 면역억제 효과를 나타낼 수 있음이 밝혀졌다 (문헌 [D. Weltin et al., Int. J. Immunopharmacol. 1995, 17, 265-271] 참조).It has also been found that PARP inhibitors may have an immunosuppressive effect (see D. Weltin et al., Int. J. Immunopharmacol. 1995, 17, 265-271).
마찬가지로, PARP는 예를 들어 류마티스성 관절염 및 패혈성 쇼크 등과 같이 면역계가 중요한 역할을 하는 면역학적 질환 또는 질병에 관여하며, PARP 억제제는 상기 질병의 진행에 유리한 효과를 나타낼 수 있다는 것도 밝혀졌다 (문헌 [H. Kroeger et al., Inflammation 1996, 20, 203-215], 문헌 [W. Ehrlich et al., Rheumatol. Int. 1995, 15, 171-172], 문헌 [C. Szabo et al., Proc. Natl. Acad.Sci. USA 1998, 95, 3867-3872], 문헌 [S. Cuzzocrea et al., Eur. J. Pharmacol. 1998, 342, 67-76] 참조).Likewise, PARP is involved in immunological diseases or diseases in which the immune system plays an important role, such as, for example, rheumatoid arthritis and septic shock, and it has also been found that PARP inhibitors can have a beneficial effect on the progression of the disease. H. Kroeger et al., Inflammation 1996, 20, 203-215, W. Ehrlich et al., Rheumatol. Int. 1995, 15, 171-172, C. Szabo et al., Proc Natl.Acad. Sci. USA 1998, 95, 3867-3872, S. Cuzzocrea et al., Eur. J. Pharmacol. 1998, 342, 67-76.
또한, PARP 억제제인 3-아미노벤즈아미드는 순환계 기능부전 모델에서 보호 효과를 나타냈다 (문헌 [S. Cuzzocrea et al., Br. J. Pharmacol. 1997, 121, 1065-1074] 참조).In addition, 3-aminobenzamide, a PARP inhibitor, has shown a protective effect in a circulatory dysfunction model (see S. Cuzzocrea et al., Br. J. Pharmacol. 1997, 121, 1065-1074).
마찬가지로, PARP 효소 억제제가 진성 당뇨병 치료용 작용제로서 유용할 수 있다는 실험적 증거가 있다 (문헌 [V. Burkhart et al., Nature Med. 1999, 5, 314-319] 참조).Similarly, there is experimental evidence that PARP enzyme inhibitors may be useful as agents for treating diabetes mellitus (see V. Burkhart et al., Nature Med. 1999, 5, 314-319).
프탈라진 및 그의 유도체는 널리 사용되는 물질들의 클래스이다. 그러나, 4번 위치에 치환체를 추가로 갖는 2H-프탈라진-1-온은 현재까지 널리 개시되지 않았다. 그러므로, 메틸렌아미드, 메틸렌우레아 및 메틸렌이미드는 문헌 [Puodzhyunas et al., Pharm. Chem. J. 1973, 7, 566], 문헌 [W. Mazkanowa et al., Zh. Obshch. Khim. 1958, 28, 2822] 및 문헌 [F.K. Mohamed et al., Ind. J. Chem. B, 1994, 33, 769]에 기술되어 있다. 아미노 기가 시클릭 아민 및 지방족 아민 둘 다일 수 있는 시클릭 아민 및 알킬아민에 관한 것은, 항-죽상경화 (粥狀硬化) 효과, 혈액 혈소판 응집 억제 또는 혈압 저하에 대해 조사한 것이긴 하지만, 문헌 [J. Singh et al., Ind. J. Chem. B, 1983, 22, 1083], 문헌 [Y. Egushi et al., Chem Pharm. Bull. 1991, 9, 1846] 및 문헌 [Iyo Kizai Kenkyusho Hokoku, 1998, 12, 41 (CA 91, 91579)]에 기술되어 있다. WO 99/11649는 4번 위치에 페닐피페라지닐메틸 라디칼을 갖는 프탈라지논에 대해 언급하면서, 이를 PARP 효소 억제제로 기술하고 있다.Phthalazine and its derivatives are a class of widely used materials. However, 2H-phthalazin-1-one further having a substituent at position 4 has not been widely disclosed to date. Therefore, methyleneamide, methyleneurea and methyleneimide are described by Puudzhyunas et al., Pharm. Chem. J. 1973, 7, 566, W. Mazkanowa et al., Zh. Obshch. Khim. 1958, 28, 2822 and F.K. Mohamed et al., Ind. J. Chem. B, 1994, 33, 769. Regarding the cyclic amines and alkylamines in which the amino group may be both cyclic and aliphatic amines, although investigations have been made on anti-atherogenic effects, inhibition of blood platelet aggregation or lowering blood pressure, J. . Singh et al., Ind. J. Chem. B, 1983, 22, 1083, Y. Egushi et al., Chem Pharm. Bull. 1991, 9, 1846 and Iyo Kizai Kenkyusho Hokoku, 1998, 12, 41 (CA 91, 91579). WO 99/11649 describes phthalazinone having a phenylpiperazinylmethyl radical at position 4 and describes it as a PARP enzyme inhibitor.
4번 위치에 페녹시메틸 유도체를 갖는 2H-프탈라지논은 문헌 [A.M. Bernard et al., Synthesis 1998, 317]에 따라 제조된다.2H-phthalazinone having a phenoxymethyl derivative at position 4 is described in A.M. Bernard et al., Synthesis 1998, 317.
놀랍게도, 본 발명은 PARP 억제제인 하기 화학식 I의 신규 프탈라진 유도체에 관해 기술한다.Surprisingly, the present invention relates to novel phthalazine derivatives of formula (I) which are PARP inhibitors.
또한 놀랍게도, 이러한 화학식 I의 화합물들은 PARP 상동성 효소 역시 억제한다는 것이 밝혀졌다. 또한 놀랍게도, 이 화합물들은 PARP 상동성 효소를 선택적으로 억제하는데, 즉, 이 화합물들은 PARP 효소 그 자체보다 그의 상동성 효소를 더 강력하게 억제한다.It has also been found that these compounds of formula I also inhibit PARP homologous enzymes. Also surprisingly, these compounds selectively inhibit PARP homologous enzymes, ie these compounds inhibit their homologous enzymes more strongly than the PARP enzyme itself.
본 발명에 따른 프탈라진은 공지된 PARP (PARP1)에 대해서보다 PARP 상동체 (PARP2)에 대해 5 배 더 강력한 억제 효과를 나타내는 것이 바람직하다.The phthalazine according to the present invention preferably exhibits a five times stronger inhibitory effect on PARP homologues (PARP2) than on known PARP (PARP1).
특히, PARP 상동체란 WO 99/64572에서 청구되는 PARP2 상동체 (인간 PARP2)를 의미한다. 이것은 인간 뇌, 심장, 골격근, 신장 및 간으로부터 유리하게 단리할 수 있다. 다른 조직 및 기관에서는 인간 PARP2의 발현이 뚜렷하게 적다.In particular, PARP homologs refer to PARP2 homologues (human PARP2) as claimed in WO 99/64572. It can be advantageously isolated from human brain, heart, skeletal muscle, kidney and liver. In other tissues and organs, expression of human PARP2 is markedly low.
인간 뇌로부터 단리할 수 있는 인간 PARP2, 및 그의 기능적 등가물은 졸중 억제제 개발에 있어서 특히 바람직한 작용제이다. 이는 지시제로서 PARP2 기재의 활성 물질을 개발하는 것이 인간 뇌에 사용하기에 최적인 억제제 개발을 가능케 할 것이라 추측되기 때문이다. 그러나, PARP2를 기재로 개발된 억제제는 다른 기관에서 PARP가 매개하는 병리적 상태의 요법에도 사용될 수 있다. 본 발명에 따른 단백질 조직 분포를 바탕으로, 특히 관심있는 징후로는 적절한 기관의 허혈 상태 (뇌의 허혈 (졸중), 심장의 허혈 (심근경색), 경색 라이시스 (예를 들면, TPA, 레테플라제 (Reteplase), 또는 기계적 레이저 또는 로타블레이터 등을 사용) 중에 및 후에 발생한 손상, 및 심장 판막 대체술, 동맥류 절제술 및 심장 이식 중에 및 후에 발생한 미소경색, 신장 손상 (급성 신부전증, 급성 신장 부전, 또는 신장 이식 중에 및 후에 발생하는 손상), 간 또는 골격근 손상) 등이 있다. 또한, 허혈, 외상 (두개뇌외상), 다량 출혈, 거미막하 출혈 및 졸중 후에 발생하는 신경퇴행성 질병, 및 다중-경색 치매, 알쯔하이머병, 헌팅톤병 등과 같은 신경퇴행성 질병, 및 간질, 특히 전신성 간질 발작, 예를 들면 소발작 및 강직간대성 발작, 및 국소성 간질 발작, 예를 들면 측두엽 및 복합적인 국소성 발작의 치료 및 예방도 고려할 수 있다. 또한, 상기 단백질들은 매우 좁은 관상 동맥의 혈관재생 치료 및 매우 좁은 말초 동맥, 예를 들면 다리 동맥의 혈관재생 치료에도 사용될 수 있다. 또한, 상기 단백질들은 종양의 화학요법 및 전이 예방, 및 류마티스성 관절염 등과 같은 류마티스성 질환 및 염증 치료에서도 역할을 할 수 있다. 이들 기관 및 기타 기관들의 다른 병리적 상태도 고려할 수 있다.Human PARP2, and its functional equivalents, that can be isolated from the human brain are particularly preferred agents in the development of stroke inhibitors. This is because the development of PARP2 based actives as indicators is expected to enable the development of inhibitors that are optimal for use in the human brain. However, inhibitors developed based on PARP2 can also be used in the treatment of pathological conditions mediated by PARP in other organs. Based on the protein tissue distribution according to the invention, signs of particular interest are the ischemic state of the appropriate organs (ischemia of the brain (stroke), ischemia of the heart (myocardial infarction), infarct lysis (e.g. TPA, retepla) Damage during and after reteplase, or using a mechanical laser or rotatable, and microinfarction, kidney damage (acute renal failure, acute renal failure, during and after heart valve replacement, aneurysm and heart transplantation) Or injuries that occur during and after kidney transplantation), or liver or skeletal muscle damage). In addition, neurodegenerative diseases that occur after ischemia, trauma (cranial trauma), massive bleeding, subarachnoid hemorrhage and stroke, and neurodegenerative diseases such as multi-infarct dementia, Alzheimer's disease, Huntington's disease, and epilepsy, especially systemic epileptic seizures The treatment and prevention of, for example, small and tonic tonic seizures, and local epileptic seizures, such as temporal lobes and multiple local seizures, are also contemplated. The proteins can also be used for the revascularization of very narrow coronary arteries and for the regeneration of very narrow peripheral arteries, such as the leg arteries. The proteins may also play a role in the chemotherapy and metastasis of tumors, and in the treatment of rheumatic diseases and inflammation such as rheumatoid arthritis. Other pathological conditions of these and other organs can also be considered.
PARP2의 활성화 메카니즘은 PARP1의 것과 상이한 것으로 추정되지만, 이 효소가 손상된 DNA에 의해 활성화된다는 점에서는 PARP1과 유사하다. 이는 DNA 복구에 중요한 효소라는 것을 고려할 수 있다. 또한, 본 발명에 따른 PARP 억제는 암 등에서의 징후 (예를 들면, 종양 환자의 방사선 민감화)에도 유리할 것이다.The activation mechanism of PARP2 is believed to be different from that of PARP1, but is similar to PARP1 in that this enzyme is activated by damaged DNA. It can be considered that this is an important enzyme for DNA repair. In addition, inhibition of PARP according to the present invention will also be beneficial for indications in cancer and the like (eg, radiation sensitization of tumor patients).
본 발명에서는 PARP1 및 PARP2의 결합 파트너에 대해 상기 기술한 특이적 분석 시스템을 사용하여 상기 단백질들의 활성적 및 선택적 억제제를 개발했다.The present invention has developed active and selective inhibitors of these proteins using the specific assay systems described above for the binding partners of PARP1 and PARP2.
본 발명에 따라 제공되는 억제제는 PARP2에 대해 매우 두드러진 억제 활성을 갖는다. 이 경우의 Ki값은 예를 들어 약 700 nM 미만, 약 100 nM 미만, 및 약 30 nM 미만, 예를 들면 약 1 내지 20 nM 등과 같이 약 1000 nM 미만일 수 있다.Inhibitors provided according to the invention have very pronounced inhibitory activity against PARP2. K i values in this case may be less than about 1000 nM, such as, for example, less than about 700 nM, less than about 100 nM, and less than about 30 nM, for example, about 1-20 nM, and the like.
놀랍게도, 본 발명에 따른 바람직한 억제제는 PARP2에 대해 두드러진 선택성을 갖는다. 그러므로, 본 발명에 따른 억제제의 Ki(PARP1) : Ki(PARP2) 비는 예를 들어 5 보다 크다. PARP1 및 PARP2를 동시에 억제하는 다른 군의 억제제를 개발했다.Surprisingly, preferred inhibitors according to the invention have a pronounced selectivity for PARP2. Therefore, the K i (PARP1): K i (PARP2) ratio of the inhibitor according to the invention is for example greater than 5. Another group of inhibitors have been developed that simultaneously inhibit PARP1 and PARP2.
재조합 핵산 구조물 또는 재조합 유전자 구조물이 적절한 숙주 생물에서 발현되도록 하기 위해, 상기 구조물을 이들이 그 숙주에서 최적으로 발현되게 하는 숙주 특이적 벡터로 유리하게 삽입했다. 벡터는 당업자에게 공지되어 있고, 예를 들면 문헌 ["Cloning Vectors", Pouwels P.H. et al., editors, Elsevier, Amsterdam-New York-Oxford, 1985]에서 찾을 수 있다. 벡터란 플라스미드 이외에도 당업자에게 공지된 다른 모든 벡터, 예를 들면, 파지, SV40, CMV, 바쿨로바이러스 및 아데노바이러스 등의 바이러스, 트랜스포손 (transposon), 삽입요소 (IS element), 파스미드 (phasmid), 코스미드, 및 선형 또는 환형 DNA 등을 의미한다. 상기 벡터들은 숙주 생물에서 자동 복제되거나 염색체 복제시 자동 복제될 수 있다.In order for recombinant nucleic acid constructs or recombinant gene constructs to be expressed in an appropriate host organism, the constructs are advantageously inserted into host specific vectors that allow them to be optimally expressed in that host. Vectors are known to those skilled in the art and are described, for example, in "Cloning Vectors", Pouwels P.H. et al., editors, Elsevier, Amsterdam-New York-Oxford, 1985. In addition to plasmids, vectors are all other vectors known to those skilled in the art, such as viruses such as phage, SV40, CMV, baculovirus and adenovirus, transposons, IS elements, phasmids. , Cosmid, and linear or cyclic DNA. The vectors can be replicated automatically in host organisms or upon chromosome replication.
구조물의 발현Expression of the construct
상기 기술한 본 발명에 따른 재조합 구조물을 적절한 숙주 시스템에 도입하여 발현시키는 것이 유리하다. 이와 관련해서, 당업자에게 공지되어 있는 통상적 클로닝 방법 및 형질감염 방법을 사용하여 상기 핵산을 특정 발현 시스템에서 발현시키는 것이 바람직하다. 적절한 시스템은 예를 들어 문헌 [Current Protocols in Molecular Biology, F. Ausubel et al., editors, Wiley Interscience, New York, 1997]에 기술되어 있다.It is advantageous to introduce and express the recombinant constructs according to the invention described above in a suitable host system. In this regard, it is desirable to express the nucleic acid in a specific expression system using conventional cloning and transfection methods known to those of skill in the art. Suitable systems are described, for example, in Current Protocols in Molecular Biology, F. Ausubel et al., Editors, Wiley Interscience, New York, 1997.
원칙적으로, 적절한 숙주 생물은 본 발명에 따른 핵산, 그의 대립유전자 변이체, 그의 기능적 등가물 또는 유도체의 발현 또는 재조합 핵산 구조물의 발현을 가능케하는 모든 생물이다. 숙주 생물이란 예를 들어 박테리아, 진균, 효모, 식물 세포 또는 동물 세포 등을 의미한다. 바람직한 생물로는 에쉐리히아 (Escherichia) 속에 속하는 박테리아, 예를 들면, 대장균 (Escherichia coli), 스트렙토마이세스 (Streptomyces), 바실러스 (Bacillus) 또는 슈도모나스 (Pseudomonas), 사카로마이세스 세레비지애 (Saccharomyces cerevisiae), 아스페르질루스 (Aspergillus) 등과 같은 진핵 미생물, Sf9 또는 CHO 세포 등과 같은 동물 또는 식물의 고등 진행 세포 등이 있다.In principle, suitable host organisms are all organisms which allow for the expression of nucleic acids according to the invention, allelic variants thereof, functional equivalents or derivatives thereof or expression of recombinant nucleic acid constructs. Host organism means, for example, bacteria, fungi, yeast, plant cells or animal cells. Preferred organisms include bacteria belonging to the genus Sherry hyacinth (Escherichia) in, e.g., E. coli (Escherichia coli), Streptomyces (Streptomyces), Bacillus (Bacillus), or Pseudomonas (Pseudomonas), three Levy in Saccharomyces My process jiae (Saccharomyces cerevisiae ), eukaryotic microorganisms such as Aspergillus , and advanced cells of animals or plants such as Sf9 or CHO cells.
필요하다면, 상기 유전자 생성물을 형질전환 생물, 특히 마우스, 양 등의 형질전환 동물 또는 형질전환 식물 등에서 발현시킬 수도 있다. 상기 형질전환 생물은 돌연변이 또는 부분적 또는 완전한 결실 등에 의해 상응하는 내인성 유전자가 차단 (switch off)된 소위 녹아웃 (knockout) 동물 또는 식물일 수도 있다.If necessary, the gene product may be expressed in transgenic organisms, in particular transgenic animals such as mice, sheep, or transgenic plants. The transgenic organism may be a so-called knockout animal or plant in which the corresponding endogenous gene has been switched off by mutation or partial or complete deletion or the like.
숙주 생물 및 그 생물에 적합한 벡터, 예를 들어 플라스미드, 바이러스 또는 파지, 예를 들어 RNA-폴리머라제/프로모터 시스템을 갖는 플라스미드, 파지 λ, μ또는 다른 적당한 파지 또는 트랜스포손 및 (또는) 다른 유리한 조절 서열의 조합물이 발현 시스템을 형성한다. 발현 시스템이라는 용어는 바람직하게는 CHO 세포 등의 포유동물 세포와 pcDNA3neo 벡터 등과 같이 포유동물 세포에 적절한 벡터의 조합물을 의미한다.Vectors suitable for the host organism and the organism, for example plasmids, viruses or phages, for example plasmids having a RNA-polymerase / promoter system, phage λ, μ or other suitable phage or transposon and (or) other advantageous modulation Combinations of sequences form the expression system. The term expression system preferably means a combination of mammalian cells, such as CHO cells, and vectors suitable for mammalian cells, such as pcDNA3neo vectors and the like.
상기 기술한 바와 같이, 상기 유전자 생성물을 형질전환 생물, 마우스, 양 등의 형질전환 동물 또는 형질전환 식물 등에서 발현시킬 수도 있다. 마찬가지로, 상기 핵산에서 유도된 RNA를 이용한 무세포 (cell-free) 번역 시스템을 계획할 수도 있다.As described above, the gene product may be expressed in transgenic animals, mice, transgenic animals such as sheep or transgenic plants. Likewise, a cell-free translation system using RNA derived from the nucleic acid can be designed.
항체의 제조Preparation of Antibodies
항-PARP2 항체는 당업자에게 통상적인 방식으로 제조한다. 항체란 폴리클로날 항체, 모노클로날 항체, 인간 항체 또는 인간화 항체 또는 그의 단편, 단쇄 항체 또는 그밖의 합성 항체, 및 Fv, Fab 및 F (ab')2등의 항체 단편을 의미한다. 적절한 제조 방법은 문헌 [Campbell, A.M., Monoclonal Antibody Technology (1987), Elsevier Verlag, Amsterdam, New York, Oxford) 및 문헌 [Breitling, F. 및 Duebel, S., Rekombinante Antikoerper (1997), Spektrum Akademischer Verlag, Heidelberg] 등에 기술되어 있다.Anti-PARP2 antibodies are prepared in a manner conventional to those skilled in the art. Antibodies refer to polyclonal antibodies, monoclonal antibodies, human antibodies or humanized antibodies or fragments thereof, single chain antibodies or other synthetic antibodies, and antibody fragments such as Fv, Fab, and F (ab ') 2 . Suitable methods of preparation are described in Campbell, AM, Monoclonal Antibody Technology (1987), Elsevier Verlag, Amsterdam, New York, Oxford) and Breitling, F. and Duebel, S., Rekombinante Antikoerper (1997), Spektrum Akademischer Verlag, Heidelberg et al.
실시예 A: PARP2 cDNA의 단리Example A: Isolation of PARP2 cDNA
본 발명에 따른 cDNA 서열을 인간 뇌 cDNA 라이브러리의 cDNA 클론 (인간 뇌5' 스트레치 플러스 cDNA 라이브러리, # HL3002a, Clontech 제품)을 서열분석하면서 처음으로 발견했다. 이 클론의 서열은 상기에 서열 1로 기술되어 있다.The cDNA sequence according to the invention was first discovered by sequencing the cDNA clone of the human brain cDNA library (human brain 5 ′ stretch plus cDNA library, # HL3002a from Clontech). The sequence of this clone is described above as SEQ ID NO: 1.
실시예 B: 효소의 제조Example B Preparation of Enzymes
비교하기 위해서, 인간 PARP1을 당업자에게 통상적인 방식으로 바쿨로바이러스 시스템에서 재조합 발현시키고, 문헌 [Shah et al., Analytical Biochemistry, 1995, 227, 1-13]에 기술된 바와 같이 부분적으로 정제했다. 순도 30-50％의 소 PARP1 (c = 0.22 mg/ml, 25℃에서 총 단백질의 비활성 (比活性)은 ADP-리보스 170 nmol/min/mg)을 BIOMOL로부터 구입 (주문 번호: SE-165)했다. 인간 PARP2를 바쿨로바이러스 시스템 (Bac-to-Bac 시스템, BRL LifeScience 제품)에서 재조합 발현시켰다. 이러한 목적을 위해서, 상응하는 cDNA를 pFASTBAC-1 벡터로 클로닝했다. 대장균에서의 재조합으로 재조합 바쿨로바이러스 DNA를 제조한 후, 이 재조합 바쿨로바이러스 DNA를 곤충 세포 (Sf9 또는 하이파이브 (high five))에 형질감염시켰다. 상응하는 단백질이 발현됨을 웨스턴 블럿팅으로 검증했다. 당업자에게 통상적인 방식으로 바이러스 균주를 증폭시켰다. 바이러스를 사용하여 MOI (감염다중도; 세포에 대한 바이러스의 비율) 5-10으로 곤충 세포 배양물 (2 ×106세포/ml) 500 ml을 감염시키고 3 내지 4 일 동안 인큐베이션시켜 다량의 재조합 단백질을 발현시켰다. 그 다음, 상기 곤충 세포를 원심분리로 펠렛화하고, 이 펠렛으로부터 상기 단백질을 정제했다.For comparison, human PARP1 was recombinantly expressed in a baculovirus system in a manner customary to those skilled in the art and partially purified as described in Shah et al., Analytical Biochemistry, 1995, 227, 1-13. Purity 30-50% bovine PARP1 (c = 0.22 mg / ml, total protein inactivation at 25 ° C. was ADP-ribose 170 nmol / min / mg) from BIOMOL (Order No .: SE-165) did. Human PARP2 was recombinantly expressed in the baculovirus system (Bac-to-Bac system, BRL LifeScience). For this purpose, the corresponding cDNA was cloned into the pFASTBAC-1 vector. After recombinant baculovirus DNA was produced by recombinant in Escherichia coli, the recombinant baculovirus DNA was transfected into insect cells (Sf9 or high five). Western blotting was confirmed that the corresponding protein was expressed. Viral strains were amplified in a manner customary to those skilled in the art. Using a virus to infect 500 ml of insect cell culture (2 × 10 6 cells / ml) with MOI (multiplicity of infection; ratio of virus to cells) 5-10 and incubate for 3-4 days to incubate large amounts of recombinant protein Was expressed. The insect cells were then pelleted by centrifugation and the protein was purified from this pellet.
당업자에게 통상적인, 전형적인 단백질 정제 방법으로 단백질을 정제하고,적절한 특이적 항체를 사용하여 효소를 검출했다. 또한 일부의 경우, 상기 단백질들을 문헌 [Burtscher et al., Anal Biochem 1986, 152:285-290]에 기술되어 있는 바와 같이 3-아미노벤즈아미드 친화성 컬럼상에서 친화성 정제했다. 순도는 90％보다 높았다.Proteins were purified by typical protein purification methods conventional to those skilled in the art and enzymes were detected using appropriate specific antibodies. In some cases, the proteins were also affinity purified on a 3-aminobenzamide affinity column as described in Burtscher et al., Anal Biochem 1986, 152: 285-290. Purity was higher than 90%.
실시예 C: PARP2의 활성 및 PARP1 및 PARP2에 대한 이펙터들의 억제 효과를 측정하기 위한 분석 시스템Example C: Assay System for Measuring Activity of PARP2 and Inhibitory Effect of Effectors on PARP1 and PARP2
a) 폴리(ADP-리보스)에 대한 항체의 제조a) Preparation of Antibody Against Poly (ADP-Ribose)
폴리(ADP-리보스)를 항원으로 사용하여 항-폴리(ADP-리보스) 항체를 생성할 수 있다. 항-폴리(ADP-리보스) 항체의 제조 방법은 문헌 [Kanai Y et al. (1974) Biochem Biophys Res Comm 59:1, 300-306; Kawamaitsu H et al. (1984) Biochemistry 23, 3 77 1-3777; Kanai Y et al. (1978) Immunology 34, 501-508]에 기술되어 있다.Poly (ADP-ribose) can be used as an antigen to generate anti-poly (ADP-ribose) antibodies. Methods of preparing anti-poly (ADP-ribose) antibodies are described in Kanai Y et al. (1974) Biochem Biophys Res Comm 59: 1, 300-306; Kawamaitsu H et al. (1984) Biochemistry 23, 3 77 1-3777; Kanai Y et al. (1978) Immunology 34, 501-508.
특히, BIOMOL로부터 구입한 항-폴리(ADP-리보스) 항체 (토끼에서 유도한 폴리클로날 항혈청 항체, 주문 번호: SA-276)를 사용했다. 또한, 항-폴리(ADP-리보스) 항체 (마우스에서 유도한 모노클로날 항체, 클론 1OH, 하이브리도마 상층액을 친화성 정제하여 얻음)도 사용했다.In particular, an anti-poly (ADP-ribose) antibody (rabbit-derived polyclonal antiserum antibody, order number: SA-276) purchased from BIOMOL was used. In addition, anti-poly (ADP-ribose) antibodies (mouse-induced monoclonal antibodies, clone 1OH, hybridoma supernatants obtained by affinity purification) were also used.
하이브리도마 배양물의 상층액으로부터 얻은 항혈청 또는 모노클로날 항체를 단백질 A 친화성 크로마토그래피를 사용하여 당업자에게 통상적인 방식으로 정제했다.Antisera or monoclonal antibodies obtained from the supernatants of hybridoma cultures were purified in a manner customary to those skilled in the art using Protein A affinity chromatography.
b) ELISA (엘리사) 분석법b) ELISA assay
물질: 엘리사 착색제 (TMB 믹스, SIGMA 제품, T-8540)Substance: Elisa Colorant (TMB Mix, SIGMA Products, T-8540)
96-웰 마이크로타이터 플레이트 (Micro-Test IIIae 가요성 분석 플레이트, FALCON 제품, # 3912)를 히스톤 (SIGMA 제품, H-7755)으로 코팅했다. 이 목적을 위해, 히스톤을 탄산염 완충액 (0.05 M Na2HCO3, pH 9.4) 중에 50 ㎍/㎖의 농도로 용해시켰다. 마이크로타이터 플레이트 개개의 웰에 상기 히스톤 용액 150 ㎕를 넣고, 각각을 실온에서 2 시간 이상 인큐베이션시키거나 4℃에서 밤새 인큐베이션시켰다. 그 다음, 이 웰에 탄산염 완충액 중 1％ 농도의 BSA 용액 (SIGMA 제품, A-7888) 150 ㎕를 첨가하고, 실온에서 2 시간 동안 블록킹시켰다. 그 다음, 세척 완충액 (1 ×PBS 중의 0.05％ 트윈10 (Tween10); PBS (인산염완충염수, Gibco 제품, 주문 번호: 10010): KH2PO40.21 g/L, NaCl 9 g/L, Na2HPO4·7H2O 0.726 g/L, pH 7.4)으로 3 회 세척했다. 세척 단계는 모두 마이크로타이터 플레이트 세척기 ("컬럼버스 (Columbus)" 마이크로타이터 플레이트 세척기, 오스트리아 소재의 SLT-Labinstruments 제품) 중에서 수행했다.96-well microtiter plates (Micro-Test IIIae flexible assay plate, FALCON, # 3912) were coated with histone (SIGMA, H-7755). For this purpose, histones were dissolved at a concentration of 50 μg / ml in carbonate buffer (0.05 M Na 2 HCO 3 , pH 9.4). 150 μl of the histone solution was placed in individual microtiter plates and each was incubated at room temperature for at least 2 hours or at 4 ° C. overnight. 150 μl of a 1% BSA solution (SIGMA, A-7888) in carbonate buffer was then added to the wells and blocked for 2 hours at room temperature. Wash buffer (0.05% Tween10 in 1 × PBS); PBS (phosphate buffered saline, Gibco, order no .: 10010): 0.21 g / L KH 2 PO 4 , 9 g / L NaCl, Na 2 Washed three times with HPO 4 .7H 2 O 0.726 g / L, pH 7.4). The washing steps were all performed in a microtiter plate washer ("Columbus" microtiter plate washer, SLT-Labinstruments, Austria).
효소 반응에는 효소 반응 용액 및 기질 용액이 필요하였으며, 각각 프리믹스 (premix) 형태이었다. 상기 용액들의 절대량은 의도한 분석 웰 개수에 따라 다르다.The enzymatic reaction required an enzyme reaction solution and a substrate solution, each in the form of a premix. The absolute amount of the solutions depends on the intended number of assay wells.
웰 당 효소 반응 용액의 조성:Composition of enzyme reaction solution per well:
-PARP 반응 완충액 (1 M 트리스-HCl, pH 8.0, 100 mM MgCl2, 10 mM DTT) 4 ㎕4 μl of -PARP reaction buffer (1 M Tris-HCl, pH 8.0, 100 mM MgCl 2 , 10 mM DTT)
-PARP1 (인간 또는 소) 20 ng 또는 PARP2 (인간) 8 ng-PARP1 (human or bovine) 20 ng or PARP2 (human) 8 ng
-활성화 DNA (1 mg/ml, SIGMA 제품, D-4522) 4 ㎕4 μl of activated DNA (1 mg / ml, manufactured by SIGMA, D-4522)
-H2O 40 ㎕ 이하-40 μl or less of H 2 O
웰 당 기질 용액의 조성:Composition of substrate solution per well:
-PARP 반응 완충액 (10 ×) 5 ㎕-5 μL-PARP reaction buffer (10 ×)
-NAD 용액 (10 mM, SIGMA 제품, N-1511) 0.8 ㎕0.8 μl of -NAD solution (10 mM, available from SIGMA, N-1511)
-H2O 44 ㎕44 μl H 2 O
1 × PARP 반응 완충액에 억제제를 용해시켰다. 더 높은 농도의 억제제 용해에 종종 사용되는 DMSO는 최종 농도 2％까지 문제가 없었다. 각 웰에 효소 반응을 위한 효소 반응 용액 40 ㎕ 및 억제제 용액 10 ㎕를 넣고, 10 분 동안 인큐베이션시켰다. 그 다음, 각 웰에 기질 용액 50 ㎕를 첨가하여 효소 반응을 개시했다. 실온에서 30 분 동안 반응시킨 후, 세척 완충액으로 3 회 세척하여 중지시켰다.Inhibitors were dissolved in 1 × PARP reaction buffer. DMSO, which is often used to dissolve higher concentrations of inhibitors, was no problem up to 2% final concentration. In each well, 40 μl of enzyme reaction solution and 10 μl of inhibitor solution for enzyme reaction were incubated for 10 minutes. Then, 50 µl of the substrate solution was added to each well to initiate the enzyme reaction. After reacting at room temperature for 30 minutes, it was stopped by washing three times with washing buffer.
사용한 1차 항체는 1 : 5000으로 희석한 특이적 항-폴리(ADP-리보스) 항체였다. 희석은 항체 완충액 (PBS 중의 1％ BSA; 0.05％ 트윈20) 중에서 수행했다. 실온에서 1차 항체를 1 시간 동안 인큐베이션시켰다. 이어서, 세척 완충액으로 3 회 세척한 후, 2차 항체 (퍼옥시다제와 커플링된 항-마우스 IgG의 Fab 단편, Boehringer Mannheim 제품, 주문 번호: 1500.686; 퍼옥시다제와 커플링된 항-래빗 IgG, SIGMA 제품, 주문 번호: A-6154)를 항체 완충액에 1 : 10,000으로 희석하여 실온에서 1 시간 동안 인큐베이션시켰다. 세척 완충액으로 3 회 세척한 후, 웰당착색제 (TMB 믹스, SIGMA 제품) 100 ㎕를 사용하여 실온에서 약 15분 동안 착색 반응시켰다. 2M H2SO4100 ㎕를 첨가하여 착색 반응을 중지시켰다. 그 다음, 엘리사 (ELISA) 플레이트 판독기 (EAR340AT "이지 리더 (Easy Reader)", 오스트리아 소재의 SLT-Labinstruments 제품)에서 즉시 측정했다 (450 nm 대 620 nm). 측정 원리는 상기의 도 6에 도식적으로 나타나있다.The primary antibody used was a specific anti-poly (ADP-ribose) antibody diluted 1: 5000. Dilution was performed in antibody buffer (1% BSA in PBS; 0.05% Tween20). Primary antibodies were incubated for 1 hour at room temperature. Subsequently, after washing three times with washing buffer, the secondary antibody (Fab fragment of anti-mouse IgG coupled with peroxidase, Boehringer Mannheim product, order no .: 1500.686; anti-rabbit IgG coupled with peroxidase , SIGMA, Order No .: A-6154) was diluted 1: 10,000 in antibody buffer and incubated for 1 hour at room temperature. After washing three times with wash buffer, the reaction was stained for about 15 minutes at room temperature using 100 [mu] l of well-colored colorant (TMB Mix, SIGMA). 100 μl of 2M H 2 SO 4 was added to stop the coloring reaction. Subsequently, measurements were taken immediately on an ELISA plate reader (EAR340AT "Easy Reader", SLT-Labinstruments, Austria) (450 nm vs. 620 nm). The measuring principle is shown schematically in FIG. 6 above.
다양한 농도에서의 투여량-효과 플롯을 작성하여 억제제의 Ki를 결정했다. 특정한 억제제 농도에 대하여 3 회씩 반복하여 상기 값을 구했다. 마이크로소프트 (Microsoft) (등록상표) 엑셀을 사용하여 계산했다. 마이크로칼 (Microcal) (등록상표) 오리진 소프트웨어 (Origin Software) (버젼 5.0) ("S자형 피트 (Sigmoidal Fit)")를 사용하여 IC50을 결정했다. 이렇게 계산한 IC50값을 "보정 억제제 (calibration inhibitors)"를 사용하여 Ki값으로 변환시켰다. 또한 각각의 분석에서 "보정 억제제"를 측정했다. "보정 억제제"의 Ki값은 당업자에게 통상적인 방식의 딕슨 (Dixon) 도표 분석법을 사용하여 동일 분석 시스템에서 측정했다.Dose-effect plots at various concentrations were prepared to determine the K i of the inhibitor. The value was determined by repeating three times for the specific inhibitor concentration. Calculations were made using Microsoft® Excel. IC 50 was determined using Microcal® Origin Software (version 5.0) ("Sigmoidal Fit"). The calculated IC 50 values were converted to K i values using “calibration inhibitors”. In addition, "calibration inhibitors" were measured in each assay. K i values of “calibration inhibitors” were measured in the same assay system using the Dixon plot assay in a manner conventional to those skilled in the art.
c) HTRF (Homogeneous Time-Resolved Fluorescence) 분석c) Homogeneous Time-Resolved Fluorescence (HTRF) analysis
본 발명에 따른 HTRF PARP 분석에서, XL665 형광단을 사용하여 표적 단백질로서 히스톤을 표지함으로써 PARP를 간접 표지했다. 항체는 유로퓸 크립테이트 (cryptate)로 직접 표지했다. XL665 형광단이 공간상 바로 인접해 있는 경우 (이는 히스톤 상의 폴리(ADP-리보스)에 결합함으로써 가능함), 에너지 전달이 가능했다. 그러므로, 665 nm에서의 방사량은 결합한 항체의 양에 직접 비례하고, 이는 폴리(ADP-리보스)의 양에 등가였다. 그러므로, 측정된 신호는 PARP 활성에 상응했다. 측정 원리는 상기의 도 7에 도식적으로 나타나있다. 특별히 언급하지 않는한, 사용한 물질은 엘리사 (상기 참조)에 사용한 물질과 동일했다.In the HTRF PARP assay according to the invention, PARP was indirectly labeled by labeling histones as target proteins using the XL665 fluorophore. Antibodies were labeled directly with Europium cryptate. When the XL665 fluorophores were immediately adjacent in space (which is possible by binding to poly (ADP-ribose) on histones), energy transfer was possible. Therefore, the radiation at 665 nm was directly proportional to the amount of antibody bound, which was equivalent to the amount of poly (ADP-ribose). Therefore, the measured signal corresponded to PARP activity. The measuring principle is shown schematically in FIG. 7 above. Unless otherwise noted, the materials used were the same as those used for Elisa (see above).
히스톤을 헤페스 (Hepes) 완충액 (50 mM, pH =7.5) 중에 3 mg/㎖의 농도로 용해시켰다. 술포-NHS-LC-바이오틴 (Pierce 제품, # 21335T)을 사용하여 바이오틴화시켰다. 히스톤 1 몰에 대해 사용한 바이오틴의 몰비는 4였다. 실온에서 90 분 동안 인큐베이션시켰다. 그 다음, 바이오틴화된 히스톤을 헤페스 완충액 (50 mM, pH = 7.0) 중의 G25SF HR10/10 컬럼 (Pharmacia 제품, 17-0591-01) 상에서 정제하여 과량의 바이오틴화 시약을 제거했다. 이관능성 커플링 시약을 사용하여 항-폴리(ADP-리보스) 항체를 유로퓸 크립테이트로 표지했다 (문헌 [Lopez, E. et al., Clin. Chem. 39(2), 196-201 (1993), 미국 특허 제5,534,662호] 참조). G25SF HR10/30 컬럼 상에서 정제했다. 항체 1 몰에 대한 크립테이트의 몰비는 3.1이었다. 수율은 25％였다. 접합체를 인산염 완충액 (0.1 M, pH = 7) 중 0.1％ BSA의 존재하에 -80℃에서 저장했다.Histone was dissolved in Hepes buffer (50 mM, pH = 7.5) at a concentration of 3 mg / ml. Biotinylation was performed using sulfo-NHS-LC-biotin (Pierce, # 21335T). The molar ratio of biotin used per 1 mole of histone was 4. Incubate at room temperature for 90 minutes. Biotinylated histones were then purified on G25SF HR10 / 10 columns (Pharmacia, 17-0591-01) in Hepes buffer (50 mM, pH = 7.0) to remove excess biotinylation reagent. Anti-poly (ADP-ribose) antibodies were labeled with europium cryptate using a bifunctional coupling reagent (Lopez, E. et al., Clin. Chem. 39 (2), 196-201 (1993) , US Pat. No. 5,534,662). Purification on G25SF HR10 / 30 column. The molar ratio of cryptate to 1 mole of antibody was 3.1. The yield was 25%. The conjugate was stored at −80 ° C. in the presence of 0.1% BSA in phosphate buffer (0.1 M, pH = 7).
효소 반응을 위해, 각 웰에 하기의 성분을 피펫으로 첨가했다:For the enzymatic reaction, the following components were pipetted into each well:
- PARP HTRF 반응 완충액 (50 mM 트리스-HCl, pH 8.0, 10 mM MgCl2, 1 mM DTT) 중의 PARP 용액 10 ㎕ 및 PARP1 (인간 또는 소) 20 ng 또는 PARP2 (인간) 8 ng,10 μl of PARP solution in PARP HTRF reaction buffer (50 mM Tris-HCl, pH 8.0, 10 mM MgCl 2 , 1 mM DTT) and 20 ng of PARP1 (human or bovine) or 8 ng of PARP2 (human),
- PARP HTRF 반응 완충액 (50 ㎍/ml) 중의 활성화 DNA 10 ㎕10 μl of activated DNA in PARP HTRF reaction buffer (50 μg / ml)
- PARP HTRF 반응 완충액 (1.25 μM) 중의 바이오틴화된 히스톤 10 ㎕10 μl biotinylated histone in PARP HTRF reaction buffer (1.25 μM)
- PARP HTRF 반응 완충액 중의 억제제 10 ㎕10 μl of inhibitor in PARP HTRF reaction buffer
상기 시약을 2 분 동안 예비인큐베이션시킨 후에, PARP HTRF 반응 완충액 (400 μM/ml) 중의 NAD 용액 10 ㎕를 첨가하여 반응 개시했다. 실온에서 30 분 동안 반응시켰다.After the reagent was preincubated for 2 minutes, the reaction was initiated by the addition of 10 μl of a NAD solution in PARP HTRF reaction buffer (400 μM / ml). The reaction was carried out at room temperature for 30 minutes.
그 다음, "레벨레이션 (Revelation)" 완충액 (100 mM, 트리스-HCl, pH 7.2, 0.2 M KF, 0.05％ BSA) 중의 PARP 억제제 (25 μM, Ki= 10 nM) 10 ㎕를 첨가하여 반응을 중지시켰다.The reaction was then added by adding 10 μl of a PARP inhibitor (25 μM, K i = 10 nM) in “Revelation” buffer (100 mM, Tris-HCl, pH 7.2, 0.2 M KF, 0.05% BSA). Stopped.
그 다음, 하기의 성분을 첨가했다:Next, the following ingredients were added:
-EDTA 용액 (SIGMA 제품, E-7889, H2O 중 0.5 M) 10 ㎕10 μl of -EDTA solution (SIGMA, E-7889, 0.5 M in H 2 O)
-"레벨레이션" 완충액 (15-31.25 nM) 중의 Sa-XL665 (Packard Instruments 제품) 100 ㎕100 μl of Sa-XL665 (Packard Instruments) in “leveling” buffer (15-31.25 nM)
-"레벨레이션" 완충액 (1.6-3.3 nM) 중의 항-PARP 크립테이트 50 ㎕50 μl of anti-PARP cryptate in “leveling” buffer (1.6-3.3 nM)
이로부터 30 분 (최대 4 시간) 후, 측정이 가능했다. "디스커버리 HTRF 마이크로플레이트 애널라이져 (Discovery HTRF Microplate Analyzer)" (Packard Instruments 제품)를 사용하여 측정했다. 엘리사에 대해 기술된 바와 같이 Ki값을 계산했다.After 30 minutes (up to 4 hours) from this, measurements were possible. Measurements were made using a "Discovery HTRF Microplate Analyzer" (Packard Instruments). K i values were calculated as described for Elisa.
본 발명은 하기 화학식 I의 치환된 프탈라진 및 그의 호변이성질체 형태, 가능한 거울상 이성질체 형태 및 부분입체 이성질체 형태, 및 그의 전구약물의 용도에 관한 것이다.The present invention relates to substituted phthalazine and its tautomeric forms, possible enantiomeric and diastereomeric forms of the formula (I) and the use of prodrugs thereof.
상기 식에서,Where
R1은 수소, 염소, 불소, 브롬, 요오드, 분지 및 비분지 C1-C6-알킬, OH, 니트로, CF3, CN, NR11R12, NH-CO-R13, O-C1-C4-알킬이며, 이 때 R11및 R12는 서로 독립적으로 수소 또는 C1-C4-알킬이며, R13은 수소, C1-C4-알킬, 페닐-C1-C4-알킬 또는 페닐이고,R 1 is hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C 1 -C 6 -alkyl, OH, nitro, CF 3 , CN, NR 11 R 12 , NH-CO-R 13 , OC 1 -C 4 -alkyl, wherein R 11 and R 12 are independently of each other hydrogen or C 1 -C 4 -alkyl, R 13 is hydrogen, C 1 -C 4 -alkyl, phenyl-C 1 -C 4 -alkyl or Phenyl,
A1는 직쇄 또는 분지 C0-C6-알킬 라디칼이고,A 1 is a straight or branched C 0 -C 6 -alkyl radical,
A2는 NR2, NR2-C1-C6-알킬, O 및 S이고,A 2 is NR 2 , NR 2 -C 1 -C 6 -alkyl, O and S,
R2는 수소 및 C1-C6-알킬이고,R 2 is hydrogen and C 1 -C 6 -alkyl,
A3은 각각의 경우, 5 또는 6 개의 고리 원자 및 N, O, S로부터 선택된 3 개이하의 헤테로원자를 갖는 방향족 또는 헤테로방향족 고리로서, 예를 들면, 페닐, 티오펜, 피리딘, 피리미딘, 나프탈렌, 인돌, 이미다졸이고, 이는 또한 R4및 1 개 또는 2 개의 R3로 치환될 수도 있으며, 이 때 R3은 수소, 염소, 불소, 브롬, 요오드, 분지 및 비분지 C1-C6-알킬, OH, 니트로, CF3, CN, NR11R12, SO2NR11R12, SO2-C1-C4-알킬, S-C1-C4-알킬, O-Ph, O-CF3, NH-CO-R13, O-C1-C4-알킬이며, 이 때 R11및 R12는 서로 독립적으로 수소 또는 C1-C4-알킬이며, R13은 수소, C1-C4-알킬, 페닐-C1-C4-알킬 또는 페닐일 수 있고,A 3 is in each case an aromatic or heteroaromatic ring having 5 or 6 ring atoms and up to 3 heteroatoms selected from N, O, S, for example phenyl, thiophene, pyridine, pyrimidine, Naphthalene, indole, imidazole, which may also be substituted with R 4 and one or two R 3 , wherein R 3 is hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C 1 -C 6 -Alkyl, OH, nitro, CF 3 , CN, NR 11 R 12 , SO 2 NR 11 R 12 , SO 2 -C 1 -C 4 -alkyl, SC 1 -C 4 -alkyl, O-Ph, O-CF 3 , NH-CO-R 13 , OC 1 -C 4 -alkyl, wherein R 11 and R 12 are independently of each other hydrogen or C 1 -C 4 -alkyl, R 13 is hydrogen, C 1 -C 4 May be -alkyl, phenyl-C 1 -C 4 -alkyl or phenyl,
R4는 수소, (X)0,1-C1-C4-알킬-NR41R42이며, 이 때 X = O, S 및 NR43이고, R41및 R42는 서로 독립적으로 수소, C1-C6-알킬, 페닐-C1-C4-알킬 및 3 내지 7-원의 시클릭 아민일 수 있고, R43은 수소 및 C1-C4-알킬일 수 있다.R 4 is hydrogen, (X) 0,1- C 1 -C 4 -alkyl-NR 41 R 42 , wherein X = O, S and NR 43 , and R 41 and R 42 are independently of each other hydrogen, C It may be 1- C 6 -alkyl, phenyl-C 1 -C 4 -alkyl and 3 to 7-membered cyclic amine, and R 43 may be hydrogen and C 1 -C 4 -alkyl.
화학식 I의 화합물은, 라세미체, 거울상 이성질체적으로 순수한 화합물 또는 부분입체 이성질체로서 사용될 수 있다. 거울상 이성질체적으로 순수한 화합물이 요구되는 경우, 이들 화합물들은 예를 들어 적합한 광학 활성의 염기 또는 산을 사용하여 화학식 I의 화합물 또는 그의 중간체 상에서의 고전적인 라세미체 분할을 수행함으로써 얻어질 수 있다.The compounds of formula (I) can be used as racemates, enantiomerically pure compounds or diastereomers. If enantiomerically pure compounds are required, these compounds can be obtained, for example, by performing classical racemic cleavage on the compound of formula (I) or an intermediate thereof using a base or acid of suitable optical activity.
또한, 본 발명은 화학식 I의 화합물의 메소머 또는 호변이성질체인 화합물에 관한 것이다.The present invention also relates to compounds which are mesomers or tautomers of the compounds of formula (I).
또한, 본 발명은 화학식 I의 화합물과 적합한 산 또는 염기를 반응시켜 얻을 수 있는 화학식 I의 화합물의 생리적으로 허용되는 염에 관한 것이다. 적합한 산 및 염기의 예가 문헌 [Fortschritte der Arzneimittelforschung, 1966, Birkhaeuser Verlag, Volume 10, pp.224-285]에 열거되어 있다. 이들의 예로는 염산, 시트르산, 타르타르산, 락트산, 인산, 메탄술폰산, 아세트산, 포름산, 말레산, 푸마르산 등, 및 수산화나트륨, 수산화리튬, 수산화칼륨 및 트리스 등이 있다.The present invention further relates to physiologically acceptable salts of the compounds of formula (I) which are obtained by reacting a compound of formula (I) with a suitable acid or base. Examples of suitable acids and bases are listed in Fortschritte der Arzneimittelforschung, 1966, Birkhaeuser Verlag, Volume 10, pp. 224-285. Examples thereof include hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid and the like, and sodium hydroxide, lithium hydroxide, potassium hydroxide and tris.
전구약물이란 생체 내에서 화학식 I의 화합물로 대사되는 화합물을 의미한다. 전형적인 전구약물로는 아미노산, 에스테르 등의 인산염, 카르밤산염이 있다.Prodrug means a compound that is metabolized in vivo to a compound of formula (I). Typical prodrugs include phosphates, carbamates, such as amino acids and esters.
본 발명에 따른 화학식 I의 프탈라진 유도체는 문헌에서 이미 수행한 여러가지 방법으로 제조할 수 있다.The phthalazine derivatives of formula (I) according to the invention can be prepared by various methods already carried out in the literature.
가능한 합성 방법은 문헌 [Puodzhyunas et al., Pharm. Chem. J. 1973, 7, 566], 문헌 [W. Mazkanowa et al., Zh. Obshch. Khim. 1958, 28, 2822], 문헌 [F.K. Mohamed et al., Ind. J. Chem. B, 1994, 33, 769], 문헌 [J. Singh et al., Ind. J. Chem. B, 1983, 22, 1083], 문헌 [Y. Egushi et al., Chem Pharm. Bull. 1991, 9, 1846] 및 문헌 [Iyo Kizai Kenkyusho Hokoku, 1998, 12, 41 (CA 91, 91579)] 등에 기술되어 있거나 본원에서 언급했다. 본 발명에 따른 화합물은 상기에 기술된 것과 유사한 방법으로 제조할 수 있다.Possible synthetic methods are described in Puodzhyunas et al., Pharm. Chem. J. 1973, 7, 566, W. Mazkanowa et al., Zh. Obshch. Khim. 1958, 28, 2822, F.K. Mohamed et al., Ind. J. Chem. B, 1994, 33, 769, J. Singh et al., Ind. J. Chem. B, 1983, 22, 1083, Y. Egushi et al., Chem Pharm. Bull. 1991, 9, 1846 and Iyo Kizai Kenkyusho Hokoku, 1998, 12, 41 (CA 91, 91579) and the like or are referred to herein. The compounds according to the invention can be prepared by methods analogous to those described above.
본 발명에 포함되는, 화학식 I의 치환된 프탈라진은 효소인 폴리(ADP-리보스) 폴리머라제의 억제제이고, 특히 신규 PARP 상동성 효소에 대한 선택성을 나타낸다.Substituted phthalazines of the formula (I), included in the present invention, are inhibitors of the enzyme poly (ADP-ribose) polymerase and exhibit particularly selectivity for novel PARP homologous enzymes.
상기 화학식 I의 치환된 프탈라진 유도체의 억제 효과는 문헌에 기술되어 있는 효소 분석법을 이용하여 Ki값을 효과 지표로서 측정했다. 효소인 폴리(ADP-리보스) 폴리머라제 또는 PARP (EC 2.4.2.30)에 대한 상기 화학식 I의 프탈라진 유도체의 억제 효과를 이런 방식으로 측정했다.The inhibitory effect of the substituted phthalazine derivatives of the above formula (I) was determined by the K i value as an effect index using the enzyme assay described in the literature. The inhibitory effect of the phthalazine derivatives of formula (I) on the enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.30) was measured in this way.
4-(4-페닐피페라진-1-일)메틸-2H-프탈라진-1-온은 WO 99/11649에 PARP 억제제로 기술되었으며, 이는 본 발명에 따른 화합물과 구조적으로 관련이 있다. 이 화합물을 상기에서 PARP1 억제 효과 측정에 사용했던 HTRF 분석법으로 조사했다. 그러나, 이 화합물은 단지 약한 효과만을 나타냈다 (10 μM일 때 38％ 억제함).4- (4-phenylpiperazin-1-yl) methyl-2H-phthalazin-1-one has been described in WO 99/11649 as a PARP inhibitor, which is structurally related to the compound according to the invention. This compound was investigated by the HTRF assay used for measuring PARP1 inhibitory effect above. However, this compound showed only a weak effect (38% inhibition at 10 μM).
놀랍게도, 본 발명에 따른 화합물이 PARP 효소를 억제할 뿐 아니라, 뚜렷하게 더 효과적임이 밝혀졌다 (표 참조).Surprisingly, it has been found that the compounds according to the invention not only inhibit the PARP enzyme, but also are markedly more effective (see table).
화학식 I의 치환된 프탈라진 유도체는 폴리(ADP-리보스) 신타제 (PARS)라고도 알려져 있는 폴리(ADP-리보스) 폴리머라제 (PARP)의 억제제이므로, 이들 효소의 활성 증가와 관련이 있는 질병의 치료 및 예방에 이용할 수 있다.Substituted phthalazine derivatives of Formula (I) are inhibitors of poly (ADP-ribose) polymerase (PARP), also known as poly (ADP-ribose) synthase (PARS), and therefore are associated with increased activity of these enzymes. It can be used for treatment and prevention.
화학식 I의 화합물을 사용하여 허혈 후의 손상 치료 및 다양한 기관에서 예상되는 허혈 예방용 약물을 제조할 수 있다.The compounds of formula (I) can be used to prepare drugs for treating ischemia after injury and for preventing ischemia that is expected in various organs.
그러므로, 본 발명에 따른 화학식 I의 프탈라진 유도체는 허혈, 외상 (두개뇌외상), 다량 출혈, 거미막하 출혈 및 졸중 후에 발생하는 신경퇴행성 질병, 및 다중-경색 치매, 알쯔하이머병, 헌팅톤병 등과 같은 신경퇴행성 질병, 및 간질, 특히 전신성 간질 발작, 예를 들면 소발작 및 강직간대성 발작, 및 국소성 간질 발작, 예를 들면 측두엽 및 복합적인 국소성 발작의 치료 및 예방에 사용될 수 있으며, 또한, 심허혈 후의 심장 손상 및 신장 허혈 (예를 들면, 급성 신장 부전, 급성 신부전증) 후의 신장 손상 또는 신장 이식 중에 및 후에 발생하는 손상의 치료 및 예방에 사용될 수 있다. 또한, 화학식 I의 화합물은 급성 심근경색 및 의약 라이시스 (예를 들면, TPA, 레테플라제, 스트렙토키나제, 또는 기계적 레이저 또는 로타블레이터 등을 사용) 중에 및 후에 발생한 손상, 및 심장 판막 대체술, 동맥류 절제술 및 심장 이식 중에 및 후에 발생한 미소경색을 치료하는 데 사용될 수 있다. 마찬가지로, 본 발명에 따른 화학식 I의 프탈라진은 PTCA 및 바이패스술 (bypass operation) 등과 같은 매우 좁은 관상 동맥의 혈관재생 치료 및 매우 좁은 말초 동맥, 예를 들면 다리 동맥의 혈관재생 치료에도 사용될 수 있다. 또한, 화학식 I의 프탈라진은 종양 및 그의 전이의 화학요법에 유용할 수 있고, 류마티스성 관절염 등과 같은 류마티스성 질환 및 염증 치료, 및 진성 당뇨병 치료에 사용될 수 있다.Therefore, the phthalazine derivatives of formula (I) according to the present invention are neurodegenerative diseases that occur after ischemia, trauma (cranial trauma), massive bleeding, subarachnoid hemorrhage and stroke, and multi-infarct dementia, Alzheimer's disease, Huntington's disease, etc. Such neurodegenerative diseases, and epilepsy, especially systemic epileptic seizures, such as small seizure and tonic tonic seizures, and local epileptic seizures, such as temporal lobe and complex regional seizures, and can also be used for cardiac ischemia It can be used for the treatment and prevention of post-cardiac damage and renal ischemia following renal ischemia (eg, acute renal failure, acute renal failure) or damage occurring during and after kidney transplantation. In addition, the compounds of formula (I) may be used to treat injuries occurring during and after acute myocardial infarction and medical lyses (eg, using TPA, reteplase, streptokinase, or mechanical laser or rotatable, etc.), and heart valve replacement. It can be used to treat microinfarctions that occur during and after aneurysm resection and heart transplantation. Likewise, the phthalazine of formula I according to the invention can be used for the treatment of angiogenesis in very narrow coronary arteries such as PTCA and bypass operation and for the treatment of angiogenesis in very narrow peripheral arteries, for example leg arteries. have. In addition, phthalazine of formula (I) may be useful for chemotherapy of tumors and their metastases and may be used to treat rheumatic diseases and inflammation, such as rheumatoid arthritis, and the treatment of diabetes mellitus.
본 발명에 따른 제약 제제는 치료 유효량의 화학식 I의 화합물 및 통상적인 제약 부형제를 포함한다.Pharmaceutical formulations according to the invention comprise a therapeutically effective amount of a compound of formula (I) and conventional pharmaceutical excipients.
국소 외용제, 예를 들면 산제, 연고제 또는 분무제인 경우, 활성 성분은 통상적인 농도로 존재할 수 있다. 통상적으로, 활성 물질은 0.001 내지 1 중량％, 바람직하게는 0.001 내지 0.1 중량％의 양으로 존재한다.In the case of topical topical preparations such as powders, ointments or nebulizers, the active ingredient may be present in conventional concentrations. Typically, the active substance is present in an amount of 0.001 to 1% by weight, preferably 0.001 to 0.1% by weight.
내복용인 경우, 상기 제제는 단일 투여로 투여된다. 단일 투여로 체중 1 kg 당 0.1 내지 100 ㎎이 투여된다. 제제는 질환의 특성 및 심각도에 따라 1일 1 회 이상 투여될 수 있다.For internal use, the agent is administered in a single dose. In a single dose, from 0.1 to 100 mg per kg body weight. The formulations may be administered one or more times a day, depending on the nature and severity of the disease.
요구되는 투여 방법에 따라, 본 발명에 따른 제약 제제는 활성 성분 및 통상적인 담체 및 희석제를 포함한다. 국소 외용을 위해, 에탄올, 이소프로판올, 에톡실화 피마자유, 에톡실화 수소화 피마자유, 폴리아크릴산, 폴리에틸렌 글리콜, 폴리에틸렌 글리콜 스테아레이트, 에톡실화 지방 알콜, 액상 파라핀, 바셀린 및 양모지 (wool fat) 등과 같은 제약 부형제를 사용할 수 있다. 내복용에 적절한 예에는 락토스, 프로필렌 글리콜, 에탄올, 전분, 활석 및 폴리비닐피롤리돈이 있다.Depending on the method of administration required, the pharmaceutical formulations according to the invention comprise the active ingredient and conventional carriers and diluents. For topical use, pharmaceutical excipients such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, liquid paraffin, petrolatum and wool fat, etc. Can be used. Examples suitable for internal use include lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone.
토코페롤 및 부틸화 히드록시아니솔, 및 부틸화 히드록시톨루엔 등과 같은 산화방지제, 향 개질 첨가제, 안정화제, 유화제 및 윤활제가 존재할 수도 있다.Antioxidants, fragrance modifying additives, stabilizers, emulsifiers and lubricants, such as tocopherol and butylated hydroxyanisole, and butylated hydroxytoluene, may also be present.
활성 성분 외에 제제 내에 존재하는 물질 및 제약 제제의 제조에 사용되는 물질은 독성학적으로 허용가능하며, 특정 활성 화합물과 상용가능하다. 제약 제제는 통상적인 부형제 및 희석제와 활성 성분의 혼합 등과 같은 통상적인 방법으로 제조된다.In addition to the active ingredients, substances present in the preparations and materials used for the preparation of pharmaceutical preparations are toxicologically acceptable and compatible with certain active compounds. Pharmaceutical formulations are prepared by conventional methods such as conventional excipients and diluents, and mixing of the active ingredient.
제약 제제는 다양한 투여 방법, 예를 들면 경구, 비경구, 예를 들면 정맥내 주입, 피하, 복강내 및 국소적으로 투여될 수 있다. 그러므로, 가능한 제공 형태는 정제, 에멀젼제, 주입 및 주사 용액제, 페이스트제, 연고제, 겔제, 크림제, 로션제, 살포제 및 분무제이다.Pharmaceutical formulations can be administered in a variety of ways of administration, eg, oral, parenteral, eg, intravenous infusion, subcutaneous, intraperitoneal and topical. Thus, possible forms of provision are tablets, emulsions, infusion and injection solutions, pastes, ointments, gels, creams, lotions, dusting agents and sprays.
실시예 1Example 1
4(N(4-히드록시페닐)아미노메틸)-2H-프탈라진-1-온4 (N (4-hydroxyphenyl) aminomethyl) -2H-phthalazin-1-one
실시예 2Example 2
4(N(4-(N,N-디메틸술파모일)페닐)아미노메틸)-2H-프탈라진-1-온4 (N (4- (N, N-dimethylsulfamoyl) phenyl) aminomethyl) -2H-phthalazin-1-one
실시예 3Example 3
4(N(4-클로로페닐)아미노메틸)-2H-프탈라진-1-온4 (N (4-chlorophenyl) aminomethyl) -2H-phthalazin-1-one
실시예 4Example 4
4(N-페닐아미노메틸)-2H-프탈라진-1-온4 (N-phenylaminomethyl) -2H-phthalazin-1-one
실시예 5Example 5
4(N(3-트리플루오로메틸페닐)아미노메틸)-2H-프탈라진-1-온4 (N (3-trifluoromethylphenyl) aminomethyl) -2H-phthalazin-1-one
실시예 6Example 6
4(N(2-시아노페닐)아미노메틸)-2H-프탈라진-1-온4 (N (2-cyanophenyl) aminomethyl) -2H-phthalazin-1-one
실시예 7Example 7
4(N(4-메톡시페닐)아미노메틸)-2H-프탈라진-1-온4 (N (4-methoxyphenyl) aminomethyl) -2H-phthalazin-1-one
실시예 8Example 8
4(N(2,4-디클로로페닐)아미노메틸-2H-프탈라진-1-온4 (N (2,4-dichlorophenyl) aminomethyl-2H-phthalazin-1-one
실시예 9Example 9
4(N(4-니트로페닐)아미노메틸)-2H-프탈라진-1-온4 (N (4-nitrophenyl) aminomethyl) -2H-phthalazin-1-one
실시예 10Example 10
4-(N(3-메틸메르캅토페닐)아미노메틸)-2 H-프탈라진-1-온4- (N (3-methylmercaptophenyl) aminomethyl) -2H-phthalazin-1-one
실시예 11Example 11
4(N(2,4-디플루오로페닐)아미노메틸)-2H-프탈라진-1-온4 (N (2,4-difluorophenyl) aminomethyl) -2H-phthalazin-1-one
실시예 12Example 12
4(N(4-페녹시페닐)아미노메틸)-2H-프탈라진-1-온4 (N (4-phenoxyphenyl) aminomethyl) -2H-phthalazin-1-one
실시예 13Example 13
4(N(4-트리플루오로메톡시페닐)아미노메틸)-2H-프탈라진-1-온4 (N (4-trifluoromethoxyphenyl) aminomethyl) -2H-phthalazin-1-one
실시예 14Example 14
4(N(4-트리플루오로메틸페닐)아미노메틸-2H-프탈라진-1-온4 (N (4-trifluoromethylphenyl) aminomethyl-2H-phthalazin-1-one
실시예 15Example 15
4(N-메틸-N-페닐아미노메틸)-2H-프탈라진-1-온 ×HC14 (N-methyl-N-phenylaminomethyl) -2H-phthalazin-1-one × HC1
실시예 16Example 16
4(S(4-클로로페닐)메르캅토메틸)-2H-프탈라진-1-온4 (S (4-chlorophenyl) mercaptomethyl) -2H-phthalazin-1-one
실시예 17Example 17
4(S(1-메틸이미다졸-2-일)메르캅토메틸)-2H-프탈라진-1-온4 (S (1-methylimidazol-2-yl) mercaptomethyl) -2H-phthalazin-1-one
실시예 18Example 18
4(N(5-메틸메르캅토-1,3,4-트리아졸-2-일)아미노메틸)-2H-프탈라진-1-온4 (N (5-methylmercapto-1,3,4-triazol-2-yl) aminomethyl) -2H-phthalazin-1-one
실시예 19Example 19
4(S(2-피리딜)메르캅토메틸)-2H-프탈라진-1-온4 (S (2-pyridyl) mercaptomethyl) -2H-phthalazin-1-one
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| PCT/EP2000/003967 WO2000067734A2 (en) | 1999-05-11 | 2000-05-03 | Use of phthalazine derivatives |
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| AU7989400A (en) * | 1999-10-01 | 2001-05-10 | Smithkline Beecham Corporation | Compounds and methods |
| ES2220753T3 (en) * | 2000-03-20 | 2004-12-16 | N-Gene Research Laboratories Inc. | AMIDOXINE DERIVATIVES OF THE PROPENCARBOXILIC ACID, PROCEDURE FOR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
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| JPS58116471A (en) | 1981-12-29 | 1983-07-11 | Nippon Kayaku Co Ltd | 4-hydroxymethyl-1-phthalazone ester derivative and its ester |
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| ITMI981671A1 (en) | 1998-07-21 | 2000-01-21 | Zambon Spa | PHTHALAZINIC DERIVATIVES INHIBITORS OF PHOSPHODISTERASE 4 |
-
1999
- 1999-05-11 DE DE19921567A patent/DE19921567A1/en not_active Withdrawn
-
2000
- 2000-05-03 SK SK1595-2001A patent/SK286676B6/en not_active IP Right Cessation
- 2000-05-03 EP EP00934980A patent/EP1231982B1/en not_active Expired - Lifetime
- 2000-05-03 TR TR2001/03236T patent/TR200103236T2/en unknown
- 2000-05-03 BR BR0010428-0A patent/BR0010428A/en not_active IP Right Cessation
- 2000-05-03 KR KR1020017014342A patent/KR20020000642A/en not_active Application Discontinuation
- 2000-05-03 HU HU0202477A patent/HUP0202477A3/en unknown
- 2000-05-03 CZ CZ20014038A patent/CZ20014038A3/en unknown
- 2000-05-03 CA CA002372704A patent/CA2372704A1/en not_active Abandoned
- 2000-05-03 DE DE50014190T patent/DE50014190D1/en not_active Expired - Lifetime
- 2000-05-03 AT AT00934980T patent/ATE357272T1/en not_active IP Right Cessation
- 2000-05-03 IL IL14614800A patent/IL146148A0/en unknown
- 2000-05-03 WO PCT/EP2000/003967 patent/WO2000067734A2/en not_active Application Discontinuation
- 2000-05-03 CN CN00808074A patent/CN1399573A/en active Pending
- 2000-05-03 AU AU50640/00A patent/AU5064000A/en not_active Abandoned
- 2000-05-03 PL PL00352150A patent/PL352150A1/en not_active Application Discontinuation
- 2000-05-03 US US09/959,404 patent/US6903098B1/en not_active Expired - Fee Related
- 2000-05-03 ES ES00934980T patent/ES2284499T3/en not_active Expired - Lifetime
- 2000-05-03 JP JP2000616761A patent/JP2003502286A/en active Pending
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2001
- 2001-10-26 BG BG106056A patent/BG106056A/en unknown
- 2001-11-08 NO NO20015462A patent/NO20015462L/en not_active Application Discontinuation
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| CN1399573A (en) | 2003-02-26 |
| EP1231982A2 (en) | 2002-08-21 |
| HUP0202477A3 (en) | 2003-02-28 |
| US6903098B1 (en) | 2005-06-07 |
| BG106056A (en) | 2002-06-28 |
| CA2372704A1 (en) | 2000-11-16 |
| HUP0202477A2 (en) | 2002-12-28 |
| DE19921567A1 (en) | 2000-11-16 |
| EP1231982B1 (en) | 2007-03-21 |
| ATE357272T1 (en) | 2007-04-15 |
| WO2000067734A3 (en) | 2002-06-20 |
| WO2000067734A2 (en) | 2000-11-16 |
| NO20015462D0 (en) | 2001-11-08 |
| DE50014190D1 (en) | 2007-05-03 |
| TR200103236T2 (en) | 2004-08-23 |
| SK286676B6 (en) | 2009-03-05 |
| BR0010428A (en) | 2002-04-30 |
| PL352150A1 (en) | 2003-07-28 |
| CZ20014038A3 (en) | 2002-06-12 |
| NO20015462L (en) | 2001-11-08 |
| ES2284499T3 (en) | 2007-11-16 |
| SK15952001A3 (en) | 2002-08-06 |
| JP2003502286A (en) | 2003-01-21 |
| IL146148A0 (en) | 2002-07-25 |
| AU5064000A (en) | 2000-11-21 |
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